Osteoporosis is a bone-wasting disease in which there is an imbalance or uncoupling between the rate of bone formation and resorption resulting in a decrease in total bone mass. As a result of this decrease in bone mass the skeleton becomes weakened and unable to bear the normal weight-bearing stresses. The effects of osteoporosis are generally seen in the weight-bearing bearing parts of the skeleton, especially the spine and hips, which can frature in the absence of trauma. Osteoporosis affects about 24 million people in the United States and 200 million people worldwide and is blamed for 2.5 million fractures a year in elderly women. The American Medical Association estimates that as many as 25% of women will suffer fractures of the hip or spine in their lifetime as a result of osteoporosis.
The current therapies for postmenopausal osteoporosis consist of treatments which are for the most part preventive; estrogen replacement, bisphosphonates, vitamin D metabolites and calcium supplements act to inhibit bone resorption associated with the onset of menopause. Estrogen replacement in these patients is quite effective in reducing further loss of bone mass but it does not induce an increase in bone mass which is needed to reduce fracture risk and pain. These treatments have little utility in the treatment of those patients with existing osteoporosis-induced loss of bone mass who have a high fracture risk and back/joint pain. Post-menopausal women with vertebral bone mass of less than 100 mg/cc would be considered below the "fracture threshold" and would be candidates for treatment with an agent which would increase bone mass and thereby restore lost bone. The present invention focuses on agents which are useful in treating bone wasting diseases by increasing an individuals bone mass and thus reducing fracture risk. The therapeutic need for this type of agent is clearly present, especially when one considers the poor patient compliance associated with estrogen replacement therapies. Modification of the immune system by pharmacologic agents is also rapidly emerging as a major area of therapeutics. While organ transplantation alone extends the lives of thousands of patients per year, disease such as diabetes mellitus, rheumatoid arthritis, multiple sclerosis and psoriasis affect millions more and have been shown to involve reactions to autoantigens. A role for immunosuppressive agents has not only been recognized in these cases but approved for therapy as well. These include Cyclosporine, FK-506, Azathioprine, adrenocorticosteroids and Methotrexate. These drugs all have serious toxicities associated with them such as renal toxicity (Cyclosporine, FK-506), leukopenia, thrombocytopenia (Azathioprine), hepatic fibrosis and cirrhosis (methotrexate) and psychoses, cataracts, glucose intolerance, bone dissolution (Adrenocorticosteroids). Clearly a need exists for an orally active specific inhibitor of T-cell function. The present invention describes agents which inhibit a crucial enzyme unique to T-cells (CD-45) and thus provide a more specific and less toxic approach to immunosuppression.
The assignees of the present invention recently filed an application Ser. No. 732,267 directed to certain novel benzylphosphonates. Such compounds were shown to have activity in treating bone wasting diseases. They are, however, structurally different from the compounds of the present invention.